Editors' ChoiceCancer Genetics

Decoding Melanoma

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Science Translational Medicine  18 May 2011:
Vol. 3, Issue 83, pp. 83ec74
DOI: 10.1126/scitranslmed.3002640

Cancer cells specialize in breaking the rules—violating the norms for cell proliferation, migration, and differentiation. One way that cancer cells accomplish this rebellion is through the accumulation of genetic mutations, which may, for example, lead to the loss of a tumor suppressor and thus further genetic instability. Defining these genetic changes, especially those that recur in multiple patients, is critical for our understanding of the pathogenesis and potential treatment of tumors.

Melanoma is a poorly understood type of skin cancer that is often diagnosed after metastasis, making it difficult to treat and frequently fatal. In a recent study, Wei et al. used whole-exome sequencing to identify genetic alterations in malignant melanoma cells. The authors selectively sequenced coding regions, which represent a small fraction of the genome, from total genomic DNA, allowing efficient examination of variants that change protein coding. They compared the exome sequences from paired unaffected tissue and metastatic melanoma tumors from 14 patients, then identified genetic variations that were unique to the tumor and not found in normal tissues from the same subject.

First, the authors looked for specific mutations that were shared between tumors from different patients and found a change at amino acid 722 in the TRRAP gene. Knockdown of TRRAP in melanoma cell lines carrying the S722F mutation resulted in increased apoptosis, supporting the idea that this mutation assists in tumor cell survival. As a second main strategy, the authors detected genes that carried more coding change mutations than would be expected by chance. This strategy identified 15 loci that had an increased rate of mutation, including the GRIN2A locus, which was somatically mutated in 32% of the melanoma tumors analyzed. GRIN2A encodes a glutamate [N-methyl-D-aspartic acid (NMDA)] receptor subunit that functions in glutamate signaling, and interestingly, a number of other genes that were highly mutated also functioned in this pathway. This unexpected result suggests that glutamate signaling is important for metastatic melanoma cells, and it is possible that novel therapeutics could target this pathway. Discovery of these previously unknown melanoma coding changes helps us to break the code of this mysterious killer.

X. Wei et al., Exome sequencing identifies GRIN2A as frequently mutated in melanoma. Nat. Genet. 43, 442–446 (2011). [PubMed]

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